Exercise provides many health benefits for metabolic diseases including obesity, type 2 diabetes mellitus, cardiovascular disease, and cancer.1-3 Previous studies have reported a 30-40% reduction of breast cancer risk in women who exercise regularly which appears to function in a dose dependent fashion.4 Moreover, women with breast cancer have an improved survival rate if they participate in regular exercise.5-8 While the link between exercise and weight loss is well established, the mechanisms by which exercise decreases rates of cancer and improves survival are not well understood.
Irisin, a recently identified myokine believed to be released from skeletal muscle following exercise, is implicated as a potential therapeutic in a variety of metabolic diseases.9 Circulating levels of irisin appear to be reduced among type II diabetes and chronic kidney disease populations, while unaffected among anorexic populations.10-12 The mechanism of irisin secretion remains controversial, although it appears circulating irisin levels are correlated with lean body mass and may be elevated by exercise or cold exposure.9, 13, 14 Irisin has gained much interest because of its ability to stimulate metabolism and mitochondrial biogenesis in adipocytes and myocytes.9, 15 In the context of cancer, circulating concentrations of irisin among cancer patients remains unknown, although data suggest irisin treatment of select obesity related cancer cell lines does not alter viability.16 
PGC1-α overexpression in muscle stimulates an increase in expression of fibronectin type III domain containing protein 5 (FNDC5), a membrane protein that is cleaved and secreted as irisin. A prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism. Hu, et al., “FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise.” Metabolism, 2012 December; 61(12):1725-38. Irisin can act on cells (e.g., white adipose cells) in culture and in vivo to stimulate UCP1 expression and a broad program of brown fat-like development. Irisin is induced with exercise in both mouse and man, and mildly increased Irisin blood levels cause an increase in energy expenditure in mice with no change in movement or food intake. This results in improvement in metabolic disorders (e.g., obesity, insulin resistance, and glucose homeostasis). See U.S. Patent Application Document No. 20130074199.
Metformin promotes irisin release from murine skeletal muscle into blood, independently of AMPK pathway activation. Li, et al., “Metformin promotes irisin release from murine skeletal muscle into blood, independently of AMPK pathway activation”, Acta Physiol. (Oxf.) 2014 Nov. 10. (epub).
Because of irisin's potent metabolic effects on several tissue types, it is conceivable that irisin may possess the ability to alter malignant characteristics similar to other myokines.17 We hypothesize that irisin, along with other myokines and circulating factors, affect the development and aggressiveness of breast cancer. The skeletal muscle secretory factors such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) have previously been shown to alter breast cancer proliferation, and aggressiveness.18, 19 While irisin has been explored in other tissue types with implications for metabolic disease, to our knowledge this is the first attempt to characterize the molecular effects of irisin in breast cancer.
Turning to prostate cancer, physical activity is beneficial for a variety of pathologies, and is regarded as a mechanism by which the development and progression of said pathologies can be alleviated or lessened. Increased body weight and fat is linked with cancer risk, and well-controlled body weight appears to be positively influential in cancer prevention (1-3, see second set set of references). It is believed that modifiable lifestyle changes and physical activity decrease the risk of prostate cancer development (4,5). In an analysis of 10,258 men, the Prostate Cancer Prevention Trial concluded that obesity (BMI≥30) is closely associated with increased risk of high-grade prostate cancer, but a decreased risk of low-grade prostate cancer (6). Moreover, acute exercise (brisk walking) a few hours per week is associated with lower mortality, post-diagnosis, in men with prostate cancer, and may inhibit or delay further progression of localized prostate cancer (7,8).
The surface of skeletal muscle expresses the trans-membrane protein, fibronectin type III domain-containing protein 5 (FNDC5), whose expression is tightly controlled by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (9). In a yet-to-be-identified fashion, the C-terminus of FNDC5 is truncated during skeletal muscle contraction (exercise and shivering), and a 112 amino acid truncated portion is released into circulation, termed irisin, after the Greek messenger goddess “Iris.” The myokine is proposed to exist biologically and function as a dimer glycosylated at residues Asn7 and Asn52, eliciting its effects after binding to an unknown ligand-specific cell surface receptor (10,11). Irisin is thought to possibly represent a therapeutic agent for obesity due to its role as a potent stimulator of metabolism in skeletal muscle through increased mitochondrial density, and browning of adipose through upregulation of uncoupling protein 1 (UPC1), dissipating cellular energy as heat via thermogenesis (9,12). It has previously been shown that irisin levels are negatively associated with age, and positively associated with BMI, muscle mass body-cell mass, and fat-free mass, and found at higher levels in lean males over obese females, but not lean females or obese males (13). It has repeatedly been shown that acute bouts of exercise greatly elevate serum irisin levels shortly following exercise, while long-term endurance training regimens do not enhance release or total levels (13-15). While irisin is believed to be beneficial, a large body of controversial evidence exists in regards to the stimulation of irisin release, and levels in select populations. Irisin levels have been shown to be decreased in type 2 diabetic individuals, increased and decreased in individuals with metabolic syndrome, and increased in obese individuals (16-21).
Exercise stimulates the release of circulating factors from muscle and adipose that influence and protect the advancement of select pathologies, some of which and their mechanisms of action remain elusive. Because skeletal muscle is involved in endocrine cross-talk with other tissues and cancers, we hypothesized that irisin may function similarly to other secretory factors released following exercise and provide benefit for prostate cancer. Our group has previously demonstrated that irisin, without post-translational modifications, reduced malignant breast epithelial cell number, migration and viability, differentially without affecting non-malignant cells (22). Moreover, non-modified irisin enhanced cell sensitivity and the cytotoxic effect of doxorubicin, while decreasing cellular uptake, lowering the effective killing dose approximately one hundred-fold (22). Interestingly, our group also found that non-modified irisin decreased activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), possibly supporting the notion that irisin may function as an anti-inflammatory cytokine to counter pro-inflammatory cytokines that potentiate cancer metastasis and aggressive development (22). Because we have previously shown that non-modified irisin had profound effects on a hormone/endocrine-related cancer (breast) and because prostate cancer is also sensitive to endocrine axes, we hypothesized that non-modified irisin may have similar effects in prostate cancer to those in breast cancer. The objective of the present study was to examine the effects of irisin on locally advanced and invasive prostate cancer aggressiveness and characteristics, along with its role as a potential therapeutic as an adjuvant treatment with a commonly used chemotherapy. Lastly, we sought to determine whether or not irisin had activity as a potential prostate cancer therapy. While the effects of irisin have been assessed in breast cancer, obesity related cancers, and other pathologies, to our knowledge these data are the first documented in prostate cancer.